Wnt5a promotes cancer cell invasion and proliferation by receptor-mediated endocytosis-dependent and -independent mechanisms, respectively

被引:51
|
作者
Shojima, Kensaku [1 ]
Sato, Akira [1 ]
Hanaki, Hideaki [1 ]
Tsujimoto, Ikuko [1 ]
Nakamura, Masahiro [2 ]
Hattori, Kazunari [3 ]
Sato, Yuji [4 ]
Dohi, Keiji [4 ]
Hirata, Michinari [4 ]
Yamamoto, Hideki [1 ]
Kikuchi, Akira [1 ]
机构
[1] Osaka Univ, Grad Sch Med, Dept Mol Biol & Biochem, Suita, Osaka 5650871, Japan
[2] Shionogi & Co Ltd, Div Diagnost, Discovery Res Lab Innovat Frontier Med, Toyonaka, Osaka 5610825, Japan
[3] Shionogi & Co Ltd, Dept Informat & Struct Based Drug Discovery, Discovery Res Lab Innovat Frontier Med, Toyonaka, Osaka 5610825, Japan
[4] Shionogi & Co Ltd, Dept Oncol & Immunol, Discovery Res Lab Innovat Frontier Med, Toyonaka, Osaka 5610825, Japan
来源
SCIENTIFIC REPORTS | 2015年 / 5卷
关键词
BETA-CATENIN; GASTRIC-CANCER; SIGNALING PATHWAY; WNT/BETA-CATENIN; MELANOMA-CELLS; BREAST-CANCER; GROWTH-FACTOR; EXPRESSION; LRP6; BINDING;
D O I
10.1038/srep08042
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Wnt5a activates the Wnt/beta-catenin-independent pathway and its overexpression is associated with tumor aggressiveness enhancing invasive activity. For this action, Wnt5a-induced receptor endocytosis with clathrin is required. Wnt5a expression was previously believed to be associated with cancer cell motility but not proliferation. Recently, it was reported that Wnt5a is also implicated in cancer cell proliferation, but the mechanism was not clear. In this study, we generated a neutralizing anti-Wnt5a monoclonal antibody (mAb5A16) to investigate the mechanism by which Wnt5a regulates cancer cell proliferation. Wnt5a stimulated both invasion and proliferation of certain types of cancer cells, including HeLaS3 cervical cancer cells and A549 lung cancer cells although Wnt5a promoted invasion but not proliferation in other cancer cells such as KKLS gastric cancer cells. mAb5A16 did not affect the binding of Wnt5a to its receptor, but it suppressed Wnt5a-induced receptor-mediated endocytosis. mAb5A16 inhibited invasion but not proliferation of HeLaS3 and A549 cells. Wnt5a activated Src family kinases (SFKs) and Wnt5a-dependent cancer cell proliferation was dependent on SFKs, yet blockade of receptor-mediated endocytosis did not affect cancer cell proliferation and SFK activity. These results suggest that Wnt5a promotes invasion and proliferation of certain types of cancer cells through receptor-mediated endocytosis-dependent and -independent mechanisms, respectively.
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页数:12
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